Year: 2026
Type: article
Abstract: C-type inactivation of voltage-gated potassium (Kv) channels is a cooperative pore-domain process following channel opening that renders Kv channels non-conductive. It is linked to conformational changes of the selectivity filter. Although activation of the voltage-sensing domains enables pore opening, it remains unclear whether inactivation-associated conformational changes are confined to the pore domain or are transferred retrogradely to the voltage sensors, including those of neighboring subunits. Here, we used voltage-clamp fluorometry in dimeric constructs of ShakerIR, the Drosophila Kv1 equivalent, to monitor conformational changes associated with C-type-inactivation in defined subunits while selectively altering the inactivation properties of neighboring subunits. We found that the fast inactivating W434F-containing subunits moved rapidly into their final voltage sensor-associated conformation, even in the presence of wildtype neighbors, indicating energetic uncoupling of voltage sensor and covalent linker movement from the S6 pore gate. However, the remaining wildtype subunits continued to follow the inactivation time course, with kinetics consistent with a concerted transition involving only the coupled wildtype subunits. These results indicate that W434F uncouples the voltage sensor from the pore gate without abolishing the cooperative pore-domain transition. We propose that C-type inactivation is governed by an entropic bottleneck in which a highly ordered collective pore-domain movement enables the final selectivity-filter rearrangement. This concerted pore-domain transition, in turn, can retrogradely constrain voltage sensor relaxation in neighboring subunits.
Source: Frontiers in Biophysics
Authors: Zerghona Shafia, Rikard Blunck
Institution: Université de Montréal
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $2,353
OpenAlex ID: W7225227959